LY294002 suppresses the malignant phenotype and sensitizes osteosarcoma cells to pirarubicin chemotherapy

Abstract

Abstract.Pirarubicin is frequently used in chemotherapy against tumors. However, clinical use is severely limited by the development of progressive dose-dependent cardiomyopathy and acquired drug resistance. LY294002 is a commonly used pharmacologic inhibitor, which selectively inhibits the phosphoinositide 3-kinase-AKT nexus. The aim of this study was to investigate the combined inhibitory effect of LY294002 and pirarubicin on human osteosarcoma (OS) cells in vitro. The inhibitory effect of LY294002 plus pirarubicin on U2-OS and MG-63 OS cell proliferation, apoptosis, migration and invasion was investigated by cell proliferation, wound healing and Transwell invasion assays. The results revealed that LY294002 and pirarubicin synergistically induced apoptosis, and inhibited the growth, migration and invasion of OS cells. This indicates that LY294002 enhanced the effects of pirarubicin on OS in vitro. LY294002 combined with pirarubicin may thus be a future therapeutic strategy in OS. IntroductionOsteosarcoma (OS) is the most common type of malignant tumor of the bone. Due to the rapid and aggressive nature of the disease, the standard treatment for OS was previously amputation of the affected limb; however, the cure rate associated with this method was <10% and almost all patients succumbed to their disease within one year from initial diagnosis. Over the past three decades, with the development of effective chemotherapeutic agents, the five-year cumulative survival rate of primary OS patients has significantly improved to 60-90% (1-7). Chemotherapy is, thus, an important treatment for OS.Pirarubicin, a member of the anthracycline family, is widely applied in the treatment of OS (8-12). However, its clinical use is severely limited by the development of progressive dose-dependent cardiomyopathy and acquired drug resistance (13). Adjunctive drug therapies occasionally reduce adverse reactions and drug resistance. Therefore, drugs that enhance the effect of pirarubicin against OS are being investigated.The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is important in tumor cell differentiation, cell cycle, apoptosis, growth and metastasis (8,9). Recent studies have shown that the PI3K/AKT signaling pathway is crucially involved in the resistance of cancer cells to chemotherapy (14,15). Therefore, inhibition of the PI3K/AKT signaling pathway is under investigation as a potential target for cancer therapy. LY294002 is a commonly used pharmacological PI3K inhibitor, which acts on the ATP-binding site of the PI3K enzyme and thus selectively inhibits the PI3K-AKT nexus. Numerous studies have demonstrated that LY294002 enhances the chemosensitivity of various cancer types to a wide variety of drugs (16)(17)(18)(19). However, whether LY294002 enhances the effects of pirarubicin on OS remains unclear.In the present study, the effect of LY294002 on the sensitivity of OS cell lines to pirarubicin chemotherapy was investigated, in addition to the possible mechanisms underlying any such effect. Materials and methodsCel...

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